Mono-N-substituted tetraaza macrocycles of general formula I ##STR1## in which n stands for the numbers 2 or 3,
R stands for a .beta.-carboxylalkyl or .beta.-carboxylate alkyl, .beta.-cyanide alkyl, .beta.-carboxamidoalkyl, .beta.-hydroxyalkyl, aminocarbonyl, aminothiocarbonyl, .beta.-sulfamoylalkyl radical or for a second tetraazacyclododecane or tetraazacyclotetradecane molecule bound by a bis(.beta.-hydroxy)-alkylene chain, and carboxyl and hydroxy groups are present optionally in protected form, PA1 R stands for a .beta.-carboxylalkyl or .beta.-carboxylate alkyl, .beta.-cyanide alkyl, .beta.-carboxamidoalkyl, .beta.-hydroxyalkyl, aminocarbonyl, aminothiocarbonyl, .beta.-sulfamoylalkyl radical or for a second tetraazacyclododecane or tetraazacyclotetradecane molecule bound by a bis(.beta.-hydroxy)-alkylene chain, and wherein carboxyl and hydroxy groups are present optionally in protected form, PA1 R meaning a ##STR4## in which R.sup.1 stands for a hydrogen atom, a straight-chain or cyclic C.sub.1 -C.sub.6 alkyl, a phenyl or benzyl group--in which the phenyl or benzyl group can be substituted respectively by 1 to 2 chlorine, bromine, nitro, C.sub.1 -C.sub.7 alkoxy, C.sub.7 -C.sub.10 aralkoxy, and/or CO.sub.2 R.sup.4 radicals with R.sup.4 meaning a hydrogen atom, a C.sub.1 -C.sub.6 alkyl, phenyl or benzyl group, PA1 R.sup.2 and R.sup.3, independent of one another each stand for R.sup.1 or a CO.sub.2 R.sup.4 group, PA1 A stands for a CN, CO.sub.2 R.sup.4 or ##STR5## in which R.sup.5 and R.sup.6, independent of one another, each stand for a hydrogen atom, a saturated or unsaturated, straight-chain, branched-chain or cyclic hydrocarbon radical with up to 16 C atoms, optionally interrupted by 1 to 8 oxygen atoms, or 1 to 3 phenylene or phenylenoxy groups, and optionally substituted by 1 to 5 hydroxy groups or 1 to 2 CO.sub.2 R.sup.4 radicals; for phenyl or benzyl radicals optionally substituted by 1 to 3 hydroxy or C.sub.1 -C.sub.6 alkoxy groups; or R.sup.5 and R6together with the nitrogen atom stand for a saturated or unsaturated 5- or 6-ring, optionally containing another nitrogen, oxygen, sulfur atom or a carbonyl group, which optionally is substituted by 1 to 3 C.sub.1 -C.sub.6 alkyl radicals optionally substituted by 1 to 3 hydroxy groups, PA1 and optionally present hydroxy and/or carboxyl groups optionally are protected, PA1 R.sup.4' stands for hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, or C.sub.6 -C.sub.10 -Ar(C.sub.1 -C.sub.4) alkyl, and PA1 the optionally present hydroxy radicals are optionally in protected form, PA1 R.sup.9 means a phenyl, 1- or 2-naphthyl or straight-chain or cyclic C.sub.1 -C.sub.6 alkyl group, PA1 Y is hydrogen or a metal ion equivalent of an element of atomic numbers 21-32, 37-39, 42-51 or 57-83 provided that at least two substituents Y stand for metal equivalents, PA1 n is 2 or 3, PA1 R.sup.12 is a ##STR14## R.sup.7 and R.sup.8, independent of one another, are each hydrogen, C.sub.1 -C.sub.20 alkyl optionally interrupted by 1 to 10 oxygen atoms, a phenylene, phenylenoxy or phenylenedioxy group, which optionally is substituted by 1 to 3 C.sub.1 -C.sub.6 alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 C.sub.1 -C.sub.7 alkoxy, 1 to 3 C.sub.7 -C.sub.10 aralkoxy, 1 to 2 CO.sub.2 R.sup.4', and/or 1 to 2 phenoxy or phenyl groups optionally substituted by 1 to 2 chloro, bromo, nitro or C.sub.1 -C.sub.6 alkoxy radicals, PA1 R.sup.4' is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl or C.sub.6 -C.sub.10 -Ar(C.sub.1 -C.sub.4)alkyl, and PA1 the optionally present hydroxy radicals optionally are present in protected form, PA1 the latter is saponified to form an intermediate of formula I' ##STR18## and the intermediate of formula I' is reacted in the presence of a base with a compound of formula X, EQU X--CH.sub.2 --COOZ (X), PA1 in which PA1 X is a leaving group, and PA1 Z is hydrogen, a carboxy protective group or a metal cation, PA1 optionally after protection of hydroxy or carboxy groups, in a polar solvent at about -10.degree. C. to 170.degree. C. within about 1-100 hours, the protecting groups are then optionally cleaved off, PA1 the thus obtained complexing agent of formula XI, ##STR19## is reacted with a metal oxide or metal salt of an element of atomic numbers 21-32, 37-39, 42-51 or 57-83 and optionally still present hydrogen atoms are also substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides or the still present acid groups are converted completely or partially into esters or amides. PA1 Y is hydrogen or a metal ion equivalent of an element of atomic numbers 21-32, 37-39, 42-51 or 57-83 provided that at least two substituents Y stand for metal equivalents, PA1 n is 2, PA1 R.sup.2 is a ##STR21## R.sup.7 and R.sup.8, independent of one another, are each hydrogen C.sub.1 -C.sub.10 alkyl optionally interrupted by 1 to 5 oxygen atoms, a phenylene, phenylenoxy or phenylenedioxy group, and which is optionally substituted by 1 to 3 C.sub.1 -C.sub.6 alkyl, 1 to 3 trifluoromethyl, 1 to 5 hydroxy, 1 to 3 C.sub.1 -C.sub.7 alkoxy, 1 to 2 CO.sub.2 R.sup.4' radicals, and/or 1 to 2 phenoxy or phenyl groups optionally substituted by a nitro group or a C.sub.1 -C.sub.6 alkoxy radical, and PA1 R.sup.4' is hydrogen, C.sub.1 -C.sub.6 alkyl or benzyl.
are important precursors of tri-N-carboxyalkyl, preferably tri-N-carboxymethyl, substituted tetraaza macrocycles, which are used as diagnostic agents and therapeutic agents in the form of their complexes with metal ions of atomic numbers 21 to 29, 31, 32, 38, 39, 42-44, 49 or 57-83 (see European patent application publication no. 255471).
Because of their importance as key compounds for these complexes, above all for the preferred NMR diagnostic agents (Macrocyclic Chemistry Congress, Hamburg 1988), production of mono-N-substituted tetraaza macrocycles has been attempted in different ways, but without a satisfactory method of synthesis previously having been found.
For example, a statistical monoalkylation or monoacylation of unsubstituted tetraaza macrocycles has been described, which, however, is not suitable at least for the production of sizable amounts of substance because of the great excess of relatively costly initial amine to be used, partially very expensive chromatographic separation of the product from the initial material as well as in most cases quite moderate yields. [see Kaden, Helv. Chim. (Swiss Chem.) Acta 69, 2081 (1986); Kimura, J. Chem. Soc. Chem. Commun. 1158 (1986); Kaden, Top. Curr. Chem. 121, 157 (1984); European patent applications no. 296522 and no. 3553450].
If it is desired--in contrast to the above-described statistical monosubstitution--to perform a specific monosubstitution, two variants are possible:
a) reaction of a tetraaza macrocycle, provided with three nitrogen protecting groups, which was obtained by statistical trisubstitution,
b) reaction of a tetraaza macrocycle, provided with three nitrogen protecting groups, which was produced by specific synthesis.
In the first-mentioned variant, the precursor carrying the protecting groups (e.g., tosylate, benzoate) on three nitrogen atoms is produced by statistical trisubstitution of an unsubstituted tetraaza macrocycle, so that the above-mentioned drawbacks of a statistical reaction, such as low yields, separating problems (particularly, in the production of sizable amounts of substance) also occur here [see, e.g., Macrocyclic Chemistry Congress, Hamburg 1988]. After the subsequent specific monosubstitution to introduce substituent R [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984): Kaden, Helv. Chim. Acta 66, 861 (1983); Basefield, Inorg. Chem. 25, 4663 (1986)], the protecting groups on the three nitrogen atoms have to be removed, e.g., by alkali metal in ammonia [Helv. Chim. Acta, 56, 2216 (1973); Helv. Chim. Acta 59, 1566 (1976); J. Org. Chem. 53, 3521 (1988)], lithium aluminum hydride [F. Voegtle; Liebigs Ann. Chem. (1977), 1344], Red-A.RTM. [E. H. Gold, J. Org. Chem. (1972), 37, 2208], Na-Hg [M. Kellog, J. Org. Chem. 1984, 49, 110], electrolysis [M. Hesse, Helv. Chim. Acta 71 (1988), 7, 1708 ] or hydrobromic acid/phenol/glacial acetic acid [N. G. Lukyanenko, Synthesis, 1988, 355]. These processes of the cleavage of the protecting groups are generally connected with poor yields, limit the batch size with respect to the amount of reagent to be used (e.g., in the Na-Hg method) and above all cannot be used in the case of substituents, which carry sensitive groups (e.g., hydroxyalkyl).
If the procedure is performed according to variant b), i.e., if it is desired to produce the tetraaza macrocycle precursor carrying protecting groups on three nitrogen atoms by specific synthesis, a start is made from two reactants, which are cyclized according to methods known in the literature [e.g., Richman, Org. Synthesis 58, 86 (1978); Atkins, J. Amer. Chem. Soc. 96, 2268 (1974)]; one of the two reactants contains a protected nitrogen atom and carries, on the chain end, two volatile groups (e.g., bromine, mesyloxy, tosyloxy, triflate or alkoxycarbonyl groups), which are nucleophilically displaced from the terminal nitrogen atoms of the second reactant, of a--unlike the first reactant--protected triaza compound.
(If a reactant with two terminal ester groups is used, the two amide groupings resulting by the cyclization--preferably with diborane in THF--have to be reduced. But especially this cyclization variant is unsuitable for the production of substantial amounts of substance, since this reaction is to be performed in the highest possible dilution, to avoid, e.g., polymerization reactions: see Tabushi, Tetrahed. Lett. 12, 1049 (1977); Kaden, Inorg. Chem. 25, 321 (1986). Also, the working up of the subsequent diborane reduction--again above all in greater batches--is not without problems.)
After cleavage of one protecting group, the thus released imino grouping can be alkylated or acylated. As an example, there can be mentioned the reaction of the disodium salt of N,N',N"-tris-(p-tolylsulfonyl)diethylene triamine [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984)] with N-bis-(2-methanesulfonyloxy-ethyl)-triphenylmethylamine in dimethylformamide at 80.degree.-150.degree. C. with subsequent cleavage of the trityl group under acid conditions. The yields of both reaction steps are generally poor. Also, this variant b) is affected with the drawbacks mentioned under a) regarding the cleavage of three protecting groups coming from the second reactant.
Besides the previously presented process of the statistical and specific monosubstitution, a specific ring synthesis, in which desired substituent R already is contained in one of the two reactants to be used in the cyclization reaction, is also possible.
Besides the problems, already described above, of the cleavage of the protecting groups, it has turned out that the thus performed cyclizations generally take place with smaller yields--as compared to the reactions of the reactant provided only with protecting groups--[see Atkins, J. Amer. Chem. Soc. 96, 2268 (1974); Richman, Org. Synthesis 58, 86 (1978); Fabbrizzi, Inorg. Chem. 25, 4131 (1986); Gazetta, Chimica Italiana 115, 399 (1985)]. Further, the reactants carrying substituent R first have to be specially synthesized in a reaction sequence often comprising several steps [see, e.g., Bulkowski, J. Org. Chem. 47, 412 (1982)].
Despite varied efforts, it therefore previously has not been possible to find a satisfactory method of synthesis for mono-N-substituted tetraaza macrocycles of general formula I, which are to be considered as key compounds for the tri-N-carboxyalkyl metal complexes being used as valuable NMR and X-ray contrast media.